title: Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2.
abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinson's disease. We employed a new, parallel, compound-centric approach to identify a potent and selective LRRK2 inhibitor, LRRK2-IN-1, and demonstrated that inhibition of LRRK2 induces dephosphorylation of Ser910 and Ser935 and accumulation of LRRK2 within aggregate structures. LRRK2-IN-1 will serve as a versatile tool to pharmacologically interrogate LRRK2 biology and study its role in Parkinson's disease.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dzamko
authors.forename: Alan
authors.initials: A
authors.lastname: Prescott
authors.forename: Paul
authors.initials: P
authors.lastname: Davies
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.forename: Qingkai
authors.initials: Q
authors.lastname: Yang
authors.forename: Jiing-Dwan
authors.initials: JD
authors.lastname: Lee
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Patricelli
authors.forename: Tyzoon K
authors.initials: TK
authors.lastname: Nomanbhoy
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D001570:Benzodiazepinones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D012694:Serine / Q000737:chemistry / Q000378:metabolism
chemical_list: D001570:Benzodiazepinones; D004791:Enzyme Inhibitors; C582847:LRRK2-IN1; D011743:Pyrimidines; D012694:Serine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases